Cross bridges account for only 20% of total ATP consumption during submaximal isometric contraction in mouse fast-twitch skeletal muscle

Zhang, Shi‐Jin; Andersson, Daniel; Sandström, Marie; Westerblad, Håkan; Katz, Abram

doi:10.1152/ajpcell.00578.2005

Cited by 51 publications

(61 citation statements)

References 45 publications

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“…Furthermore, recent evidence (47) suggests that force production is not necessarily synonymous with glucose uptake but rather metabolic demand. In the present study, we used a more physiologically relevant contraction protocol than used previously (18,25,46), specifically by using lower stimulation frequencies, train durations, and contraction rates (54). Similar to the findings of Lefort et al (29), we found no difference in force production between muscles of AMPK-KD and WT mice (Fig.…”

Section: Discussionsupporting

confidence: 86%

Skeletal muscle glucose uptake during contraction is regulated by nitric oxide and ROS independently of AMPK

Merry

Steinberg

Lynch

et al. 2010

American Journal of Physiology-Endocrinology and Metabolism

110

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Merry TL, Steinberg GR, Lynch GS, McConell GK. Skeletal muscle glucose uptake during contraction is regulated by nitric oxide and ROS independently of AMPK. Am J Physiol Endocrinol Metab 298: E577-E585, 2010. First published December 15, 2009; doi:10.1152/ajpendo.00239.2009.-Reactive oxygen species (ROS) and nitric oxide (NO) have been implicated in the regulation of skeletal muscle glucose uptake during contraction, and there is evidence that they do so via interaction with AMP-activated protein kinase (AMPK). In this study, we tested the hypothesis that ROS and NO regulate skeletal muscle glucose uptake during contraction via an AMPK-independent mechanism. Isolated extensor digitorum longus (EDL) and soleus muscles from mice that expressed a muscle-specific kinase dead AMPK␣2 isoform (AMPK-KD) and wild-type litter mates (WT) were stimulated to contract, and glucose uptake was measured in the presence or absence of the antioxidant N-acetyl-Lcysteine (NAC) or the nitric oxide synthase (NOS) inhibitor N Gmonomethyl-L-arginine (L-NMMA). Contraction increased AMPK␣2 activity in WT but not AMPK-KD EDL muscles. However, contraction increased glucose uptake in the EDL and soleus muscles of AMPK-KD and WT mice to a similar extent. In EDL muscles, NAC and L-NMMA prevented contraction-stimulated increases in oxidant levels (dichloroflourescein fluorescence) and NOS activity, respectively, and attenuated contraction-stimulated glucose uptake in both genotypes to a similar extent. In soleus muscles of AMPK-KD and WT mice, NAC prevented contraction-stimulated glucose uptake and L-NMMA had no effect. This is likely attributed to the relative lack of neuronal NOS in the soleus muscles compared with EDL muscles. Contraction increased AMPK␣ Thr 172 phosphorylation in EDL and soleus muscles of WT but not AMPK-KD mice, and this was not affected by NAC or L-NMMA treatment. In conclusion, ROS and NO are involved in regulating skeletal muscle glucose uptake during contraction via an AMPK-independent mechanism. nitric oxide; reactive oxygen species; exercise; metabolism; contraction; glucose uptake EXERCISE AND CONTRACTION INCREASE translocation of GLUT4 to the cell surface, facilitating glucose transport into skeletal muscle (55). Although the mechanism(s) by which contraction increases GLUT4 translocation and glucose uptake into skeletal muscle are not yet fully defined, there is consensus that the signals regulating this pathway are independent of the insulinsignaling pathway (31, 39). Numerous mechanisms have been implicated in regulating contraction-stimulated glucose uptake (43), and one of the most attractive and well-studied candidates is AMP-activated protein kinase (AMPK). While initial studies demonstrated that the AMPK activator 5-aminoimidazole 4-carboxamide ribonucleoside (AICAR) increased glucose uptake (17) and that increased AMPK activity during contraction correlates with glucose uptake (20, 38), disassociations between glucose uptake and contraction have also been reported (9, 34). Importantly, mice that overexpre...

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Section: Discussionsupporting

confidence: 86%

Skeletal muscle glucose uptake during contraction is regulated by nitric oxide and ROS independently of AMPK

Merry

Steinberg

Lynch

et al. 2010

American Journal of Physiology-Endocrinology and Metabolism

110

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“…Zhang et al (5) offer no mechanistic explanation for their result but suggest that it differs from previous data due to an effect of species or temperature or as a result of using submaximal activation. Points i and iii above argue against an effect of either species or temperature, and the dantrolene experiments (point iii) counter the idea that activation costs are higher at submaximal levels of activation.…”

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confidence: 70%

“…TO THE EDITOR: We are struck by the remarkable results contained in the article by Zhang et al (5). Put bluntly, if these results are independently verified, then a fundamental reappraisal of over four decades of muscle energetics will be required.…”

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confidence: 99%

“…Put bluntly, if these results are independently verified, then a fundamental reappraisal of over four decades of muscle energetics will be required. This is because Zhang et al (5) infer from their data that, under conditions of submaximal stimulation (at 30°C), ϳ80% of the metabolic cost of contraction of isolated, fasttwitch, skeletal muscle [mouse extensor digitorum longus (EDL)] is attributable to Ca 2ϩ pumping by the sarcoplasmic reticulum (SR), leaving only 20% to cross-bridge cycling. These values are roughly the converse of what is conventionally considered to be the economics of energy expenditure by active striated muscle.…”

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confidence: 99%

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Can activation account for 80% of skeletal muscle energy use during isometric contraction?

Barclay¹,

Loiselle²

2007

American Journal of Physiology-Cell Physiology

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TO THE EDITOR: We are struck by the remarkable results contained in the article by Zhang et al. (5). Put bluntly, if these results are independently verified, then a fundamental reappraisal of over four decades of muscle energetics will be required. This is because Zhang et al. (5) infer from their data that, under conditions of submaximal stimulation (at 30°C), ϳ80% of the metabolic cost of contraction of isolated, fasttwitch, skeletal muscle [mouse extensor digitorum longus (EDL)] is attributable to Ca 2ϩ pumping by the sarcoplasmic reticulum (SR), leaving only 20% to cross-bridge cycling. These values are roughly the converse of what is conventionally considered to be the economics of energy expenditure by active striated muscle. We are rather skeptical, for the following reasons.i) An unreferenced paper by Barclay (1), which employed the same muscle preparation at a comparable temperature (25°C), demonstrated that non-cross-bridge-related heat production (estimated by extrapolating to zero filament overlap the heat produced at various degrees of stretch) was 35% and was unaltered by a fatiguing protocol that reduced force to 55% of its initial value. ii) Baylor and Hollingworth (3) showed that during tetanic stimulation of mouse EDL (67 Hz at 16°C) the amount of Ca 2ϩ released per stimulus pulse was ϳ0.08 mol/g (this is an overestimate, because much more Ca 2ϩ was released by the first pulse than later pulses) and was little different at 28°C. So in the 100 pulses used by Zhang et al. (5) in a 2-s tetanus, a total of 8 mol/g Ca 2ϩ would have been released, which would require 4 mol/g ATP to be pumped into the SR. In comparison, Zhang et al. (5) measured the activation cost to be over fourfold greater: 15 mol/g. iii) In another unreferenced study (4), activation heat (once again, estimated by "extrapolation") of mouse EDL at 27°C was 35%. In the presence of a submaximal dose of dantrolene (an inhibitor of the skeletal muscle Ca 2ϩ -release channel), tetanic force was reduced to 36% of its "control" value. Nevertheless, activation heat still accounted for only 42% of the total heat liberated. iv) The idea that 20% of isometric energy turnover is due to cross-bridge cycling is incompatible with the known mechanical performance of fast-twitch muscles. If cross bridges account for only 20% of energy use, then the rate of ATP splitting per cross bridge must be one-quarter the value previously assumed. Maintenance of a high isometric force, in any cross-bridge scheme that requires a low rate of turnover, can be achieved only by reducing the rate of cross-bridge detachment. However, a low detachment rate is inconsistent with the rapid force dynamics and the flat force-velocity curve characteristic of EDL muscles (2).Zhang et al. (5) offer no mechanistic explanation for their result but suggest that it differs from previous data due to an effect of species or temperature or as a result of using submaximal activation. Points i and iii above argue against an effect of either species or temperature, and the dantrolene e...

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“…Although the impairment in Ca 2ϩ uptake at fatigue has been well described, the importance of the ATP demand on SERCA regulation during repetitive contractions leading to fatigue is controversial (2, 28). Furthermore, little is known concerning whether the ATP cost of Ca 2ϩ handling during muscle activation is sufficient to regulate the SR Ca 2ϩ uptake kinetics and function during fatiguing contractile work.Several studies have assessed SR Ca 2ϩ uptake energy cost by blocking the activation of cross-bridge cycling using the compound N-benzyl-p-toluene sulfonamide (BTS) (5,7,22,30,40). This compound inhibits the affinity between myosin and actin (23) but does not affect Ca 2ϩ release and uptake in single muscle fibers (9,30,39).…”

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confidence: 99%

Ca²⁺-pumping impairment during repetitive fatiguing contractions in single myofibers: role of cross-bridge cycling

Nogueira

Shiah

Gandra

et al. 2013

American Journal of Physiology-Regulatory, Integrative and Comp

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Nogueira L, Shiah AA, Gandra PG, Hogan MC. Ca 2ϩ -pumping impairment during repetitive fatiguing contractions in single myofibers: role of cross-bridge cycling. Am J Physiol Regul Integr Comp Physiol 305: R118 -R125, 2013. First published May 15, 2013 doi:10.1152/ajpregu.00178.2013.-The energy cost of contractions in skeletal muscle involves activation of both actomyosin and sarcoplasmic reticulum (SR) Ca 2ϩ -pump (SERCA) ATPases, which together determine the overall ATP demand. During repetitive contractions leading to fatigue, the relaxation rate and Ca 2ϩ pumping become slowed, possibly because of intracellular metabolite accumulation. The role of the energy cost of cross-bridge cycling during contractile activity on Ca 2ϩ -pumping properties has not been investigated. Therefore, we inhibited cross-bridge cycling by incubating isolated Xenopus single fibers with N-benzyl-p-toluene sulfonamide (BTS) to study the mechanisms by which SR Ca 2ϩ pumping is impaired during fatiguing contractions. Fibers were stimulated in the absence (control) and presence of BTS and cytosolic calcium ([Ca 2ϩ ]c) transients or intracellular pH (pHi) changes were measured. BTS treatment allowed normal [Ca 2ϩ ]c transients during stimulation without cross-bridge activation. At the time point that tension was reduced to 50% in the control condition, the fall in the peak [Ca 2ϩ ]c and the increase in basal [Ca 2ϩ ]c did not occur with BTS incubation. The progressively slower Ca 2ϩ pumping rate and the fall in pHi during repetitive contractions were reduced during BTS conditions. However, when mitochondrial ATP supply was blocked during contractions with BTS present (BTS ϩ cyanide), there was no further slowing in SR Ca 2ϩ pumping during contractions compared with the BTS-alone condition. Furthermore, the fall in pHi was significantly less during the BTS ϩ cyanide condition than in the control conditions. These results demonstrate that factors related to the energetic cost of cross-bridge cycling, possibly the accumulation of metabolites, inhibit the Ca 2ϩ pumping rate during fatiguing contractions. Ca 2ϩ uptake rate; skeletal muscle; cross-bridge cycling; fatigue; glycolysis; oxidative phophorylation DURING THE TRANSITION FROM rest to exercise in skeletal muscle, the demand for ATP increases several hundredfold, primarily because of the activation of both actomyosin (i.e., cross-bridge cycling) and sarcoplasmic reticulum (SR) Ca 2ϩ ATPase (SERCA) pumps (6). After membrane depolarization, cytosolic Ca 2ϩ concentration is transiently increased, thereby elevating actomyosin and SERCA ATPase activities. Although the Na ϩ -K ϩ -ATPase activity has a high contribution in the energy cost at rest [ϳ40% of total; (27)], it is quite small during contractions [ϳ1.5-7%; (6)]. Conversely, during contractions, actomyosin ATPase and SERCA account for ϳ60% and 40% of the total ATP demand, respectively (5,6,22,30). However, the energy cost of Ca 2ϩ handling by SERCA during contractions may be as high as 80% of the total energy cost in type IIB...

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Cross bridges account for only 20% of total ATP consumption during submaximal isometric contraction in mouse fast-twitch skeletal muscle

Cited by 51 publications

References 45 publications

Skeletal muscle glucose uptake during contraction is regulated by nitric oxide and ROS independently of AMPK

Skeletal muscle glucose uptake during contraction is regulated by nitric oxide and ROS independently of AMPK

Can activation account for 80% of skeletal muscle energy use during isometric contraction?

Ca²⁺-pumping impairment during repetitive fatiguing contractions in single myofibers: role of cross-bridge cycling

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Cross bridges account for only 20% of total ATP consumption during submaximal isometric contraction in mouse fast-twitch skeletal muscle

Cited by 51 publications

References 45 publications

Skeletal muscle glucose uptake during contraction is regulated by nitric oxide and ROS independently of AMPK

Skeletal muscle glucose uptake during contraction is regulated by nitric oxide and ROS independently of AMPK

Can activation account for 80% of skeletal muscle energy use during isometric contraction?

Ca2+-pumping impairment during repetitive fatiguing contractions in single myofibers: role of cross-bridge cycling

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Ca²⁺-pumping impairment during repetitive fatiguing contractions in single myofibers: role of cross-bridge cycling